International Journal of Cardiology 250 (2018) 62–63

Contents lists available at ScienceDirect

International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Editorial

Serum uric acid and acute coronary syndrome: Is there a role for
functional markers of residual cardiovascular risk?
C. Borghi ⁎, A.F.G. Cicero
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

a r t i c l e i n f o Once again, the results of the present study are in agreement with
experimental evidence reporting a negative effect of hyperuricemia
Article history: in several models of ischemia-reperfusion [5] complicated by SUA-
Received 16 May 2017
related cardiac damage. Uric acid is the final step of a complex biochem-
Accepted 13 June 2017
ical cascade aimed at the catabolism of purines [1,2]. The key enzymatic
step responsible for the production of SUA is the activation of the
Keywords: Xanthine-Oxide-Reductase system (XOR) that is directly responsible
Uric acid for the production of uric acid in association with a remarkable oxida-
Oxidative stress tive stress [1]. This pro-oxidant effect has probably a causative role in
Acute coronary syndrome
the negative cardiovascular effects described for elevated uric acid
in patients with and without cardiovascular disease. Conversely, the
possibility of a direct vascular effect of elevated SUA (or better of urate
Both clinical and experimental evidence has been published during
crystal) is hard to support since the threshold value for CV events re-
the last decade supporting the existence of a close relationship between
ported in most of the literature seems to be significantly lower than
elevated levels of serum uric acid (SUA) and hypertension, metabolic
the physiological level for tissue urate deposition (actually N6.5 mg/dL).
diseases, chronic kidney disease and cardiovascular events [1,2]. The
From the mechanistic point of view, the pro-oxidative effects associ-
negative cardiovascular effects of raised SUA levels have been demon-
ated with SUA production can negatively affect endothelial function,
strated in patients with gout [1] as well as in the larger population of
blood pressure control, renal function as well as left ventricular perfor-
subjects with asymptomatic hyperuricemia after adjustment for almost
mance [1,2]. A close relationship between SUA levels and left ventricular
all the common risk factors [2]. The detrimental effects of elevated SUA
ejection fraction has been described in patients with established con-
have been confirmed also in patients with overt cardiovascular disease
gestive heart failure of ischemic origin [6]. In addition, the oxidative
including heart failure [3], atrial fibrillation [2] and coronary artery
mechanism underlying the production of uric acid can increase the
disease [1,2]. The clinical evidence has been largely supported by exper-
negative impact of common cardiovascular risk factors that are largely
imental data obtained in different animal models [1,2] by showing a
represented in patients with asymptomatic hyperuricemia. In particu-
close correlation between the increase in SUA and some structural and
lar, the elevated plasma levels of uric acid have been linearly correlated
functional abnormalities of the cardiovascular system. This progressive
to the higher rate of LDL oxidation (ox-LDL) [7] leading to an over-
increase in the availability of information has led to an increase in the
expression of tissue angiotensin type-1 receptors [8] that can contribute
quantity of resources dedicated to a better definition of the diagnostic
to the negative effects of hyperuricemia in patients with and without
role of serum uric acid as a potential biomarker in addition to the
cardiovascular diseases including those with ACS. The interaction be-
well-established risk factors.
tween ox-LDL and the activation of tissue renin-angiotensin system
In the present issue of the International Journal of Cardiology,
can reduce the stability of the atherosclerotic plaques [9] and promote
Cianflone and colleagues [4] have reported the results of a retrospective
the activation of the inflammatory pathway [1] with an increase in the
study aimed at the definition of the prognostic role of increasing levels of
risk of vascular complications (Fig. 1), as demonstrated by the positive
SUA in 1548 patients hospitalized with a confirmed diagnosis of ACS in-
correlation between UA, C-reactive protein concentrations and in-
cluding ST-elevation myocardial infarction (STEMI), NSTEMI and unsta-
hospital deaths observed in the study of Cianflone and co-workers [4].
ble angina. In these patients, a multivariate logistic regression suggested
The complexity of this pathogenetic mechanism could reasonably
a significant increase in the risk of in-hospital mortality when SUA levels
explain the excess in the risk of death and major CV events observed
on admission were N 6.0 mg/dL thus again confirming the importance of
in subjects bearing SUA levels within or outside the so called “normal
elevated SUA in patients with established cardiovascular disease.
range” (usually b 6 mg/dL). Because of this close interaction with
oxidative stress, serum uric acid could play a major role as a “functional
DOI of original article: http://dx.doi.org/10.1016/j.ijcard.2017.04.027.
⁎ Corresponding author at: Internal Medicine Unit, 4th Floor, Building 2, S. Orsola-
marker” of a residual cardiovascular risk at least in those subgroups
Malpighi University of Bologna, Italy. of patients where over-production is the main mechanism respon-
E-mail address: claudio.borghi@unibo.it (C. Borghi). sible for the increased plasma levels of uric acid. A hypothesis of a

http://dx.doi.org/10.1016/j.ijcard.2017.06.053
0167-5273/© 2017 Elsevier B.V. All rights reserved.
 Editorial
Fig. 1. Schematic summary of the main pathways activated by oxidative stress associated with uric acid production and cardiovascular disease.
2-component system controlling for the increased plasma levels in SUA
has been already proposed in the literature [10] and could represent
a reliable explanation for the clinical differences among subjects
with comparable serum levels of uric acid. This clearly suggests the
importance of an accurate identification of the different sub-types of
patients with elevated SUA paying special attention to those belong-
ing to the “hyper-productive” subset who are also candidate to the
treatment with xanthine-oxidase inhibitors [7]. This population should
reasonably include the patients without history of gout, with normal
renal function, not treated with drugs affecting SUA, and the female
patients whose renal urate reabsorption is significantly limited by the
inhibitory effect of oestrogens on the renal tubular mechanisms.
In conclusion, a careful consideration of all the available evidence
clearly supports the relevant involvement of serum uric acid at various
levels in the natural history of cardiovascular diseases. This could be the
consequence of the oxidative stress associated with XO activity and
urate production and we are all looking for a reliable test that could
allow the clinical interpretation of SUA levels with the aim of preventing
the negative impact of hyperuricemia that Cianflone and co-workers
have very well described in their interesting paper.
Conflict of interest
The authors report no relationships that could be construed as a
conflict of interest.
63
References
[1] D.I. Feig, D.H. Kang, R.J. Johnson, Uric acid and cardiovascular risk, N. Engl. J. Med.
359 (2008) 1811–1821.
[2] C. Borghi, E. Agabiti-Rosei, T. Bardin, J. Dawson, A. Dominiczak, J.T. Kielstein, et al.,
Serum uric acid and the risk of cardiovascular and renal disease, J. Hypertens. 33
(2015) 1729–1741.
[3] S.D. Anker, W. Doehner, M. Rauchhaus, R. Sharma, D. Francis, C. Knosalla, C.H. Davos,
M. Cicoira, W. Shamim, M. Kemp, R. Segal, K.J. Osterziel, F. Leyva, R. Hetzer, P.
Ponikowski, A.J. Coats, Uric acid and survival in chronic heart failure: validation
and application in metabolic, functional, and hemodynamic staging, Circulation
107 (15) (2003) 1991–1997.
[4] M. Magnoni, M. Berteotti, F. Ceriotti, V. Mallia, V. Vergani, G. Peretto, G. Angeloni, N.
Cristell, A. Maseri, D. Cianflone, Serum uric acid on admission predicts in-hospital
mortality in patients with acute coronary syndrome, Int. J. Cardiol. 240 (2017)
25–29.
[5] P. Pacher, A. Nivorozhkin, C. Szabó, Therapeutic effects of xanthine oxidase inhibitors:
renaissance half a century after the discovery of allopurinol, Pharmacol. Rev. 58 (1)
(Mar 2006) 87–114.
[6] C1. Borghi, E.R. Cosentino, E.R. Rinaldi, A.F. Cicero, Uricaemia and ejection fraction in
elderly heart failure outpatients, Eur. J. Clin. Investig. 44 (6) (Jun 2014) 573–578.
[7] A.F. Cicero, M. Rosticci, M. Cagnati, R. Urso, G. Scapagnini, M. Morbini, E. Grandi, S.
D'Addato, C. Borghi, Brisighella Heart Study Group, Serum uric acid and markers
of low-density lipoprotein oxidation in nonsmoking healthy subjects: data from
the Brisighella Heart Study, Pol. Arch. Med. Wewn. 124 (12) (2014) 661–668.
[8] L.O. Lerman, A. Lerman, All oxidase roads lead to angiotensin, too, Arterioscler.
Thromb. Vasc. Biol. 27 (4) (Apr 2007) 703–704.
[9] Y. Saito, T. Nakayama, K. Sugimoto, Y. Fujimoto, Y. Kobayashi, Relation of lipid con-
tent of coronary plaque to level of serum uric acid, Am. J. Cardiol. 116 (9) (2015)
1346–1350.
[10] K. Ichida, H. Matsuo, T. Takada, A. Nakayama, K. Murakami, T. Shimizu, Y. Yamanashi,
H. Kasuga, H. Nakashima, T. Nakamura, Y. Takada, Y. Kawamura, H. Inoue, C. Okada, Y.
Utsumi, Y. Ikebuchi, K. Ito, M. Nakamura, Y. Shinohara, M. Hosoyamada, Y. Sakurai, N.
Shinomiya, T. Hosoya, H. Suzuki, Decreased extra-renal urate excretion is a common
cause of hyperuricemia, Nat. Commun. 3 (Apr 3 2012) 764.